UC Davis

Few classes of natural products have inspired as many chemists and biologists as have the iboga alkaloids. This family of monoterpenoid indole alkaloids includes the anti-addictive compound ibogaine as well as catharanthine, a precursor to the chemotherapeutic vinblastine. Despite being known for over 120 years, these small molecules continue to challenge our assumptions about biosynthetic pathways, catalyze our creativity for constructing complex architectures, and embolden new approaches for treating mental illness. While significant progress regarding their chemistry and pharmacology has been made since the 1960s, there is an emerging need for the development of an efficient and scalable total synthesis of these alkaloids. Access to iboga alkaloids by means of isolation has been hindered by low yields and environmental challenges. Thus, an efficient and modular total synthesis would enable widespread access for analog development and biological testing. Accordingly, we have developed a facile 5-7 step total synthesis that allows for the preparation of ibogaine and a variety of related alkaloids and analogs. Using substrate-induced radical selectivity, our synthesis offers multiple points for diversification to aid in analog library development. An asymmetric variant has also been developed to provide unprecedented access to both enantiomers of the iboga scaffold.